1. Greater New York City RDRC Meeting, December 2007 1 PROGRAM UPDATE - Radioactive Drug Research Committee CAPT Richard Fejka, USPHS, RPh, MS, BCNP Senior Manager - Radioactive Drug Research Committee program Division of Medical Imaging and Hematology Products Office Of Oncology Drug Products Center for Drug Evaluation and Research U.S. Public Health Service CAPT Richard Fejka, USPHS, RPh, MS, BCNP Senior Manager - Radioactive Drug Research Committee program Division of Medical Imaging and Hematology Products Office Of Oncology Drug Products Center for Drug Evaluation and Research U.S. Public Health Service

2. Greater New York City RDRC Meeting, December 2007 2 OutlineOutline History Regulation Research Under an RDRC Monitoring Reporting Forms Current Status of Committees, Study Summaries and Regulatory Initiatives Annual Report Reviews - Observations History Regulation Research Under an RDRC Monitoring Reporting Forms Current Status of Committees, Study Summaries and Regulatory Initiatives Annual Report Reviews - Observations

3. Greater New York City RDRC Meeting, December 2007 3 A Little History Prior to 1975 AEC (Atomic Energy Commission) regulated reactor produced radioactive drugs January 8, 1963 Federal Register notice temporarily exempted radioactive new drugs for investigational use from requirements of part 312

4. Greater New York City RDRC Meeting, December 2007 4 A Little History (continued) The purpose of the exemption was to allow Federal agencies to explore ways to avoid unnecessary duplication of regulatory control AEC and FDA concluded ALL radioactive drugs should now be subject to the same clearance procedures as other drugs

5. Greater New York City RDRC Meeting, December 2007 5 A Little History (continued) FDA established regulations on August 25, 1975 to regulate ALL radioactive drugs Determined that all radioactive drugs are either New Drugs or GRAS/E (Generally Recognized As Safe and Effective) ALL radioactive drugs now subject to an IND, NDA or biological product license EXCEPT radioactive drugs used for certain research uses

6. Greater New York City RDRC Meeting, December 2007 6 The Regulation 21 CFR 361Prescription Drugs for Human Use Generally Recognized as Safe and Effective and Not Misbranded: Drugs Used In Research § 361.1 Radioactive drugs for certain research uses.

7. Greater New York City RDRC Meeting, December 2007 7 The Regulation (a) Radioactive drugs (…) are generally recognized as safe and effective when administered, under the conditions set forth in paragraph (b) of this section, to human research subjects during the course of a research project intended to obtain basic information regarding the metabolism (including kinetics, distribution, and localization) of a radioactively labeled drug or regarding human physiology, pathophysiology, or biochemistry, but not intended for immediate therapeutic, diagnostic, or similar purposes or to determine the safety and effectiveness of the drug in humans for such purposes (i.e., to carry out a clinical trial). Certain basic research studies, e.g., studies to determine whether a drug localizes in a particular organ or fluid space and to describe the kinetics of that localization, may have eventual therapeutic or diagnostic implications, but the initial studies are considered to be basic research within the meaning of this section.

8. Greater New York City RDRC Meeting, December 2007 8 Research Under an RDRC Four conditions set in § 361.1 1.Basic Science Research 2.Pharmacological dose limit 3.Radiation dose limits 4.Radioactive Drug Research Committee Four conditions set in § 361.1 1.Basic Science Research 2.Pharmacological dose limit 3.Radiation dose limits 4.Radioactive Drug Research Committee

9. Greater New York City RDRC Meeting, December 2007 9 MonitoringMonitoring FDA conducts periodic reviews of approved committees by: Review of their annual report, Review of meeting minutes, Review of full protocols for certain studies, On-site inspections. FDA conducts periodic reviews of approved committees by: Review of their annual report, Review of meeting minutes, Review of full protocols for certain studies, On-site inspections.

10. Greater New York City RDRC Meeting, December 2007 10 MonitoringMonitoring Submit Annual Report by January 31 for past calendar year’s activities consists of FDA FORM 2914 Membership Summary and EACHFDA Form 2915 Study Summary for EACH study overseen by RDRC Submit Annual Report by January 31 for past calendar year’s activities consists of FDA FORM 2914 Membership Summary and EACHFDA Form 2915 Study Summary for EACH study overseen by RDRC

11. Greater New York City RDRC Meeting, December 2007 11 Reporting Forms Membership (2914) and Study Summary (2915) available through FDA RDRC website at http://www.fda.gov/cder/regulatory/RDRC/default.htm or 1. Go to www.fda.gov 2. Search on “RDRC” 3. Click on Radioactive Drug Research Committee (RDRC) Program 4. Click on RDRC Forms and Checklist or go to FDA’s Electronic Forms Numerical Listing page at: http://www.fda.gov/opacom/morechoices/fdaforms/default.html Membership (2914) and Study Summary (2915) available through FDA RDRC website at http://www.fda.gov/cder/regulatory/RDRC/default.htm or 1. Go to www.fda.gov 2. Search on “RDRC” 3. Click on Radioactive Drug Research Committee (RDRC) Program 4. Click on RDRC Forms and Checklist or go to FDA’s Electronic Forms Numerical Listing page at: http://www.fda.gov/opacom/morechoices/fdaforms/default.html

12. Greater New York City RDRC Meeting, December 2007 12 Reporting Forms Old Forms New Forms No instructions Dates for submission of past qualifications statements lacking Use of “dose” confusing “Maximum amount (i.e. mg) of nonradioactive moiety administered per subject, per single dose and/or the minimum specific activity (i.e. mCi/mg) of drug at the time of administration.” Terms not only confusing, but incorrect: “mR/whole body” No instructions Dates for submission of past qualifications statements lacking Use of “dose” confusing “Maximum amount (i.e. mg) of nonradioactive moiety administered per subject, per single dose and/or the minimum specific activity (i.e. mCi/mg) of drug at the time of administration.” Terms not only confusing, but incorrect: “mR/whole body” Provide Instructions Requires a Study ID number Requires a study approval and termination date Dose terms clarified, e.g. - Pharmacological and NOEL* dose (* No Observed Effect Level ) - Activity administered MBq - uCi, mCi - Radiation absorbed dose mSv - Rem

13. Greater New York City RDRC Meeting, December 2007 13 Current Status on Committees and Study Summary Reports 201 RDRCs approved Calendar Year # of RDRCs expected to report # of Study Summaries submitted for review 200384397 200481487 200578602 200673671 200775-

14. Greater New York City RDRC Meeting, December 2007 14 Status of RDRC Regulatory Initiatives Draft Guidance – being reviewed Reinstituted Inspection Program Impact of Exploratory IND Draft Guidance – being reviewed Reinstituted Inspection Program Impact of Exploratory IND

15. Greater New York City RDRC Meeting, December 2007 15 Some Observations Annual Report Reviews RDRC not associated with a medical institution. Medical institution did not know they had an RDRC. An RDRC chair who tried to convince their administration that RDRC members were surrogate FDA employees and therefore operate independently of the medical institution. An RDRC which believed that one of their roles was to review their institution’s IRB actions. Inappropriate approval of First-In-Human studies under RDRC authority. RDRC not associated with a medical institution. Medical institution did not know they had an RDRC. An RDRC chair who tried to convince their administration that RDRC members were surrogate FDA employees and therefore operate independently of the medical institution. An RDRC which believed that one of their roles was to review their institution’s IRB actions. Inappropriate approval of First-In-Human studies under RDRC authority.

16. Greater New York City RDRC Meeting, December 2007 16 Some Observations Annual Report Reviews Failure of RDRC to meet quarterly. Meeting minutes which do not show RDRC members recusing themselves from voting on studies which they are associated with. Failure to convert RDRC study into IND. Special Summary Reports not filed, or not filed in timely manner. Reluctance to use human biodistribution data to verify animal radiation dosimetry estimates. Failure of RDRC to meet quarterly. Meeting minutes which do not show RDRC members recusing themselves from voting on studies which they are associated with. Failure to convert RDRC study into IND. Special Summary Reports not filed, or not filed in timely manner. Reluctance to use human biodistribution data to verify animal radiation dosimetry estimates.

17. Greater New York City RDRC Meeting, December 2007 17 Some Observations Annual Report Reviews Membership Lack of timely notification of membership changes. Incomplete qualification documentation for membership category, especially when switching from one category to another. Radiation Dose Failure to report associated x-ray doses. Incomplete or lack of reference for dosimetry calculations. Inconsistency in dosimetry among investigators within an RDRC – obvious failure of RDRC to standardize. Membership Lack of timely notification of membership changes. Incomplete qualification documentation for membership category, especially when switching from one category to another. Radiation Dose Failure to report associated x-ray doses. Incomplete or lack of reference for dosimetry calculations. Inconsistency in dosimetry among investigators within an RDRC – obvious failure of RDRC to standardize.

18. Greater New York City RDRC Meeting, December 2007 18 If you need assistance: CAPT Richard Fejka USPHS, RPh, MS, BCNP Senior Manager, RDRC Program Richard.Fejka@FDA.HHS.GOV (301) 796-1353 Susan Lange, ARRT (R)(N), MPH Project Manager, RDRC Program Susan.Lange@FDA.HHS.GOV (301) 796-4117 Orhan Suleiman MS, PhD, FAAPM, Senior Science Policy Advisor Orhan.Suleiman@FDA.HHS.GOV (301) 796-1471 CAPT Richard Fejka USPHS, RPh, MS, BCNP Senior Manager, RDRC Program Richard.Fejka@FDA.HHS.GOV (301) 796-1353 Susan Lange, ARRT (R)(N), MPH Project Manager, RDRC Program Susan.Lange@FDA.HHS.GOV (301) 796-4117 Orhan Suleiman MS, PhD, FAAPM, Senior Science Policy Advisor Orhan.Suleiman@FDA.HHS.GOV (301) 796-1471